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US20190247305A1 - Oral suspension comprising telmisartan - Google Patents

Oral suspension comprising telmisartan Download PDF

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Publication number
US20190247305A1
US20190247305A1 US16/394,610 US201916394610A US2019247305A1 US 20190247305 A1 US20190247305 A1 US 20190247305A1 US 201916394610 A US201916394610 A US 201916394610A US 2019247305 A1 US2019247305 A1 US 2019247305A1
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Prior art keywords
pharmaceutical solution
drinkable
telmisartan
drinkable pharmaceutical
solution
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US10537523B2 (en
Inventor
Detlef Mohr
Stefan Lehner
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Boehringer Ingelheim Vetmedica GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a pharmaceutical solution, preferably a drinkable pharmaceutical solution with a pH of 10 or more containing an angiotensin-II-receptor antagonist, preferably the active substance telmisartan, as well as one or more sugar alcohols added in order to improve flavour and shelf life, wherein the content of reducing sugars before the addition of the sugar alcohol or alcohols to the solution does not exceed 1000 ppm.
  • an angiotensin-II-receptor antagonist preferably the active substance telmisartan
  • sugar alcohols added in order to improve flavour and shelf life
  • angiotensin-II-receptor antagonist which is licensed for the treatment of hypertension and is available in tablet form in different dosage strengths.
  • angiotensin-II-receptor antagonist licensed for the treatment of hypertension and is available in tablet form in different dosage strengths.
  • domestic pets such as dogs and cats it would theoretically be possible to administer tablets, but often the tablets are held in the animal's cheek pouches and spat out again later, thus seriously impairing the dosage reliability.
  • a drinkable solution free from organic cosolvents, which may be administered in controlled amounts using suitable calibrated dosing aids such as dosage sprays, pipettes, spoons or cups.
  • suitable calibrated dosing aids such as dosage sprays, pipettes, spoons or cups.
  • flavour improvers which is advantageous particularly for long-term administration for treating hypertension.
  • the aim of the present invention is to provide a pharmaceutical solution, preferably a drinkable pharmaceutical solution containing an angiotensin-II-receptor antagonist.
  • Preferred angiotensin II receptor antagonists are the substances known by the following INN names: candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan and valsartan, and the pharmaceutically acceptable salts, hydrates or polymorphs thereof.
  • the concentration of the angiotensin-II-receptor antagonist, preferably telmisartan, needed in the solution in order to achieve therapeutic doses should be between 1 mg/ml and 10 mg/ml.
  • an aqueous formulation should have a pH that is either less than 2 or more than 10, in order to ensure a physically stable solution.
  • the base components used for this work were first of all sodium hydroxide solution, meglumine or a combination of sodium hydroxide solution and meglumine, in order to produce a physically and chemically stable solution.
  • the use of alkali metal or alkaline earth metal carbonates/-hydrogen carbonates does not produce a sufficiently high pH in the present instance.
  • the use of ethanolamines was also ruled out in view of the administration route and target group.
  • telmisartan For masking or improving the bitter, rasping taste of telmisartan in solution, besides conventional quantities of synthetic sugar substitutes (saccharine, saccharine-Na, Na-cyclamate, acesulfame, aspartame, sucralose etc.), which have a risk of intolerance or in some cases are not internationally permitted (Na-cyclamate), sugar alcohols such as for example xylitol, maltitol, sorbitol, or mannitol were investigated for their suitability. They are not cariogenic (converted slowly into the acid) and have a low calorific value, which is a major advantage for long-term use particularly in children but also in pets.
  • sugar substitutes saccharine-Na, Na-cyclamate, acesulfame, aspartame, sucralose etc.
  • sugar alcohols such as for example xylitol, maltitol, sorbitol, or mannitol were investigated for
  • flavourings were cherry, strawberry, raspberry, tutti-frutti, currant, caramel, chocolate and mint flavourings, as well as meat and fish flavourings for animals.
  • glycerol as well as cellulose derivatives such as hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose or hydroxypropylmethylcellulose; or soluble PVP in small concentrations. Their use is not necessary but is useful for prolonging the contact times before the taste receptors are reached, and thereby further masking the bitter flavour.
  • the sugar alcohols xylitol, maltitol, sorbitol and mannitol are particularly preferred. Maltitol is particularly preferred.
  • identical results in terms of preserving effect can also be obtained with the other sugar alcohols.
  • a sugar alcohol concentration of at least 60% (percent by weight/volume) in a drinkable aqueous telmisartan solution the requirements of the USP Pharmacopoeia in a preservative load are met, but the enhanced requirements of the European Pharmacopoeia are not.
  • the criteria of the USP Preservation Loading Test are met less reliably as the concentration of active substance increases, but can be demonstrated up to an active concentration of 4 mg/ml.
  • the threshold value of less than 300 ppm of reducing sugar in the maltitol corresponds to less than 300 mg of reducing sugar per kg of maltitol, or less than 0.3 mg of reducing sugar per gram (g) of maltitol.
  • a 60% sugar alcohol solution (i.e. 60 g sugar alcohol per 100 ml of solution) thus should contain at most 18 mg of reducing sugar per 100 ml or 0.18 mg reducing sugar per ml of drinkable solution.
  • the threshold value represents, for example, for a
  • the content of reducing sugars should be less than 20 percent by weight, preferably less than 10 percent by weight and particularly preferably less than 5 percent by weight.
  • telmisartan solution is dependent on the amount of reducing sugar contained in the sugar alcohol.
  • the stability of a drinkable telmisartan solution deteriorates as the content of reducing sugars increases. Acidic breakdown products are formed resulting in a drop in the pH within the solution, which finally leads to the precipitation of the telmisartan as soon as the pH falls below 9.5/9.0.
  • sugar alcohols such as e.g.
  • a correspondingly prepared aqueous drinkable telmisartan solution is stable for long periods. It thus has a storage stability of at least 12 months at 25° C./60% RH (relative humidity) and 30° C./70% RH, preferably at least 36 months at 25° C./60% RH and 30° C./70% RH.
  • a quantity of reducing sugars of at least 250 ppm has a positive effect on the stability of the active substance. Consequently, a content of a maximum content of 1000 ppm, preferably between 300 ppm and 250 ppm, of reducing sugars in the pharmaceutical solution is to be regarded as being preferred.
  • a drinkable telmisartan solution prepared using a sugar alcohol with a content of reducing sugar of 300 ppm or less does not require any antioxidants or stabilizers, and their addition is thus optional.
  • aqueous drinkable telmisartan solutions in a range of concentrations from 1-10 mg/ml, preferably 1-5 mg/ml, with a pH value of ⁇ 10 or higher, a content of sugar alcohol of 40 percent by weight/volume (% W/V) or more as well as other optional formulation adjuvants above a benzalkonium chloride concentration of 0.005% W/V or higher reliably meet the requirements of the Ph.Eur. as well, while reliably masking the bitter taste of the benzalkonium chloride.
  • % W/V percent by weight/volume
  • the present invention also describes a process for preparing the drinkable telmisartan solution according to the invention containing 1-10 mg/ml telmisartan, preferably 1-5 mg/ml telmisartan. As far as possible this process also uses methods known from the literature for aqueous solutions to be taken orally.
  • the process is characterized in that a suitable amount of active substance, optionally in the form of a salt or hydrate, is combined with a molar excess of a physiologically acceptable base dissolved in water, in order to obtain a solution with a pH of ⁇ 10. Further formulation adjuvants are optionally added, and the solution is made up with purified water to obtain a concentration range of 1-10 mg of active substance per millilitre of solution. It should be noted that the solution corresponds to the properties already mentioned, particularly that of the pH value of ⁇ 10. Exemplary formulations are presented herein in Examples 1-8.
  • a consistency-providing component such as for example a cellulose derivative or PVP is pre-swollen in a given amount of purified water at ambient temperature, then heated to a temperature of 70-80° C. until fully dissolved and then adjusted to a pH of 10 by the addition of the physiologically acceptable base, while the temperature is maintained at 70-80° C.
  • the active substance is then added, with stirring, until a concentration of 1-10 mg/ml is obtained, and the sugar alcohol containing an amount of less than 1000 ppm, preferably less than 300 ppm of reducing sugar is added and dissolved. After the addition and dissolving of the sugar alcohol the solution is cooled to room temperature.
  • formulation adjuvants such as synthetic sugar substitutes, flavourings or preservatives are added at RT with stirring.
  • pH is restored to 10 using the physiologically acceptable base, before purified water is added to top up to the required weight/volume.
  • the solution can be filtered to eliminate particulate impurities, before being transferred into suitable glass or plastic bottles.
  • the drinkable telmisartan solution according to the invention exhibits high stability on storage, which is not limited either by physical instability or by breakdown reactions of the active substance, and in terms of the selected pH it is sufficiently well tolerated physiologically.
  • telmisartan 0.2 g NaOH 1N 0.68 ml maltitol* 60.0 g hydroxyethylcellulose 0.1 g purified water ad 100 ml pH 10 stability 25° C./60% RH >12 (18?) months 30° C./70% RH >12 (18?) months
  • telmisartan 0.1 g meglumine 0.6 g maltitol* 50.0 g saccharine-Na 0.6 g hydroxyethylcellulose 0.1 g purified water ad 100 ml pH 10 stability 25° C./60% RH >12 months 30° C./70% RH >12 months
  • PLT** preservation loading test
  • PLT** USP and Ph. Eur. according to USP/ Ph. Eur. * ⁇ 300 ppm red. sugar, **PLT preservation loading test
  • telmisartan 0.40 kg/100 L NaOH 1N 0.8 kg/100 L maltitol* 60.0 kg/100 L hydroxyethylcellulose 0.10 kg/100 L benzalkonium 0.01 kg/100 L % chloride purified water ad 100 L pH 10 stability 25° C./60% RH >24 months 30° C./70% RH >24 months
  • telmisartan 0.1 g meglumine q.s. ad pH 10 maltitol* 70.0 g collidone K 25 0.2 g purified water ad 100 ml pH 10 stability 25° C./60% RH >18 (12?) months 30° C./70% RH >18 (12?) months
  • telmisartan 4 mg/ml NaOH 1N 0.8 ml xylitol* 60.0 g hypromellose 0.1 g purified water ad 100 ml pH 10 stability 25° C./60% RH >12 (18?) months 30° C./70% RH >12 (18?) months Complies with PLT** USP according to USP/ Ph. Eur. * ⁇ 300 ppm red. sugar, **PLT preservation loading test
  • telmisartan (5 mg/ml) 0.5000 g NaOH 1.9000 g maltitol* 60.000 g hydroxyethylcellulose 0.1000 g purified water 59.1600 g pH 10 stability 25° C./60% RH >24 months 30° C./70% RH >24 months

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Abstract

A drinkable pharmaceutical solution includes telmisartan or a pharmaceutically acceptable salt, hydrate or polymorph thereof, where the telmisartan has a concentration of 1 to 10 mg/ml within the drinkable pharmaceutical solution, and the drinkable pharmaceutical solution has a pH of 10.

Description

    RELATED APPLICATIONS
  • This application relates to and claims priority to international patent application PCT/EP2010/056895, which was filed May 19, 2010, and to European Patent Application No. EP 09160771.3, which was filed May 20, 2009. The teachings and contents of which are incorporated herein by reference in their entirety. All applications are commonly owned.
    • FIELD OF THE INVENTION
  • The present invention relates to a pharmaceutical solution, preferably a drinkable pharmaceutical solution with a pH of 10 or more containing an angiotensin-II-receptor antagonist, preferably the active substance telmisartan, as well as one or more sugar alcohols added in order to improve flavour and shelf life, wherein the content of reducing sugars before the addition of the sugar alcohol or alcohols to the solution does not exceed 1000 ppm.
    • BACKGROUND TO THE INVENTION
  • Telmisartan, the INN name of the compound 4′-((2-n-propyl-4-methyl-6-(1-methylbenz-imidazol-2-yl)-benzimidazol-1-yl)methyl)biphenyl-2-carboxylic acid (IUPAC) having the following formula
  • Figure US20190247305A1-20190815-C00001
  • is an angiotensin-II-receptor antagonist, which is licensed for the treatment of hypertension and is available in tablet form in different dosage strengths. For use in children, particularly children under 6 years old, and in older or sick people with difficulty swallowing, it is often not possible to use tablets as a medical formulation. In domestic pets such as dogs and cats it would theoretically be possible to administer tablets, but often the tablets are held in the animal's cheek pouches and spat out again later, thus seriously impairing the dosage reliability. In addition, it is only possible to adapt dosage to weight to a limited extent, owing to the given fixed dosage steps of the tablets.
  • More suitable, and preferable from a physiological point of view, is a drinkable solution, free from organic cosolvents, which may be administered in controlled amounts using suitable calibrated dosing aids such as dosage sprays, pipettes, spoons or cups. There is also the possibility of making the formulation more acceptable to children and even pets by the addition of flavour improvers, which is advantageous particularly for long-term administration for treating hypertension.
    • SUMMARY AND DESCRIPTION OF THE INVENTION
  • The aim of the present invention is to provide a pharmaceutical solution, preferably a drinkable pharmaceutical solution containing an angiotensin-II-receptor antagonist. Preferred angiotensin II receptor antagonists are the substances known by the following INN names: candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan and valsartan, and the pharmaceutically acceptable salts, hydrates or polymorphs thereof. The concentration of the angiotensin-II-receptor antagonist, preferably telmisartan, needed in the solution in order to achieve therapeutic doses should be between 1 mg/ml and 10 mg/ml. Moreover, because of the strongly pH-dependent solubility profile of telmisartan an aqueous formulation should have a pH that is either less than 2 or more than 10, in order to ensure a physically stable solution.
  • Based on these requirements, attempts were made first of all to provide a formulation in the acid pH range, as significantly more preservatives are available for this pH range, if needed (the use of multi-dose containers for this intended application is clearly preferable).
  • The following main ingredients of the formulation were used:
      • a) pH-active components for ensuring solubility in the desired concentration range;
      • b) flavour-correcting components (sugars, sugar alcohols, sugar substitutes, flavour additives) to mask the bitter, rasping taste of telmisartan;
      • c) texture enhancers, usually viscosity-increasing adjuvants such as for example cellulose derivatives, PVP, glycerol;
      • d) preservatives for ensuring microbiological quality in the multi-dose container; and optionally
      • e) antioxidants such as for example BHA, BHT, EDTA or propylgallate for stabilizing the formulation.
  • During this development work it was found that for concentrations of active substance greater than 1 mg/ml a pH of less than 1.5 is needed, which requires the use of strong organic acids such as for example methanesulphonic acid or phosphoric acid. The very powerfully astringent effect of such acidic solutions makes acidic formulations of this kind totally unsuitable for long-term use particularly in children but also in domestic pets such as dogs and cats.
  • Further development work therefore had to be shifted to the pH range ≥10. The base components used for this work were first of all sodium hydroxide solution, meglumine or a combination of sodium hydroxide solution and meglumine, in order to produce a physically and chemically stable solution. The use of alkali metal or alkaline earth metal carbonates/-hydrogen carbonates does not produce a sufficiently high pH in the present instance. The use of ethanolamines was also ruled out in view of the administration route and target group.
  • For masking or improving the bitter, rasping taste of telmisartan in solution, besides conventional quantities of synthetic sugar substitutes (saccharine, saccharine-Na, Na-cyclamate, acesulfame, aspartame, sucralose etc.), which have a risk of intolerance or in some cases are not internationally permitted (Na-cyclamate), sugar alcohols such as for example xylitol, maltitol, sorbitol, or mannitol were investigated for their suitability. They are not cariogenic (converted slowly into the acid) and have a low calorific value, which is a major advantage for long-term use particularly in children but also in pets. Although they are suitable in principle, the use of the normal sugars (glucose, glucose syrup, fructose, saccharose, maltose, lactose etc.) is avoided because of the disadvantages mentioned above (e.g. cause of tooth decay, calorie loading).
  • Against the background of the target groups and long-term administration the addition of flavourings was largely avoided because of the potential for allergies, although it is theoretically possible to add a substance without affecting the properties of the telmisartan solution according to the invention. Examples of such flavourings are cherry, strawberry, raspberry, tutti-frutti, currant, caramel, chocolate and mint flavourings, as well as meat and fish flavourings for animals.
  • In order to improve the subjective overall impression of the telmisartan solution according to the invention (fullness/consistency/viscosity/texture) it is also possible to use glycerol as well as cellulose derivatives such as hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose or hydroxypropylmethylcellulose; or soluble PVP in small concentrations. Their use is not necessary but is useful for prolonging the contact times before the taste receptors are reached, and thereby further masking the bitter flavour.
  • There are only a very few preservatives available in suitable concentrations for the pH range of 10 and above: thus, apart from the phenol derivatives such as e.g. the cresols, which are used predominantly parenterally in the field of insulin formulations, only the quaternary ammonium compounds are available. Their toxicity must be viewed critically with regard to the target groups and long-term administration. Thus, basically, the only sufficiently acceptable option available is benzalkonium chloride, but its orally unpleasant bitter flavour represents an additional problem. Therefore investigations were carried out first of all to determine the degree to which the concentration of the sugar alcohols used was able to meet the requirements of the Pharmacopoeia regarding the Preservation Loading Test (PLT) summarized in the following Table 1.
  • TABLE 1
    Required reduction in number of
    microbes in log PFU per test microbe
    Preservation loading test
    according to USP or Ph. Eur.
    after 14 days' after 28 days'
    incubation incubation
    USP Ph. Eur. USP Ph. Eur.
    Bacteria* 1 3 no increase no increase
    Fungi** no increase 1 no increase no increase
    *E. coli, S. aureus, P. aeruginosa
    **C. albicans, A. niger
  • Because of their sweetening power and taste similarity to glucose in terms of sweet sensation the sugar alcohols xylitol, maltitol, sorbitol and mannitol are particularly preferred. Maltitol is particularly preferred. However, identical results in terms of preserving effect can also be obtained with the other sugar alcohols. Surprisingly it has been found that above a sugar alcohol concentration of at least 60% (percent by weight/volume) in a drinkable aqueous telmisartan solution the requirements of the USP Pharmacopoeia in a preservative load are met, but the enhanced requirements of the European Pharmacopoeia are not. The criteria of the USP Preservation Loading Test are met less reliably as the concentration of active substance increases, but can be demonstrated up to an active concentration of 4 mg/ml.
  • Surprisingly it has now been found that reliably meeting the criteria of the USP Preservation Loading Test and also the concentration of telmisartan and the sugar alcohol concentration are dependent on the quality of the sugar alcohol or alcohols used. Of particular importance is the quantity of reducing sugars present. A content of up to 0.2% is permitted according to the Pharmacopoeia monograph. Within the scope of our investigations it has become apparent that to ensure that the USP Preservation Loading Test is safely complied with the content of reducing sugar (primarily maltose and glucose) in the sugar alcohol, i.e. the quantity of reducing sugars in the sugar alcohol should not exceed 1000 ppm, best of all should not exceed 300 ppm, before the addition.
  • The threshold value of less than 300 ppm of reducing sugar in the maltitol corresponds to less than 300 mg of reducing sugar per kg of maltitol, or less than 0.3 mg of reducing sugar per gram (g) of maltitol.
  • A 60% sugar alcohol solution (i.e. 60 g sugar alcohol per 100 ml of solution) thus should contain at most 18 mg of reducing sugar per 100 ml or 0.18 mg reducing sugar per ml of drinkable solution.
  • The threshold value represents, for example, for a
      • 40% sugar alcohol solution less than 0.12 mg reducing sugar per ml of drinkable solution;
      • 50% sugar alcohol solution less than 0.15 mg reducing sugar per ml of drinkable solution;
      • 60% sugar alcohol solution less than 0.18 mg reducing sugar per ml of drinkable solution; or for a
      • 70% sugar alcohol solution less than 0.21 mg reducing sugar per ml of drinkable solution
  • Based on the amount of active substance of the angiotensin II receptor antagonist, preferably telmisartan, the content of reducing sugars should be less than 20 percent by weight, preferably less than 10 percent by weight and particularly preferably less than 5 percent by weight.
  • It has thus been shown that the stability of a drinkable telmisartan solution is dependent on the amount of reducing sugar contained in the sugar alcohol. The stability of a drinkable telmisartan solution deteriorates as the content of reducing sugars increases. Acidic breakdown products are formed resulting in a drop in the pH within the solution, which finally leads to the precipitation of the telmisartan as soon as the pH falls below 9.5/9.0. To obtain a telmisartan solution which is stable on storage, it is essential to add sugar alcohols such as e.g. xylitol, sorbitol or maltitol, provided that the amount of reducing sugars in the sugar alcohol of an aqueous drinkable telmisartan solution with a pH of ≥10 or higher is limited to below the content of sugar alcohols specified according to the Pharmacopoeia. A threshold value of 300 ppm or less is preferred. A correspondingly prepared aqueous drinkable telmisartan solution is stable for long periods. It thus has a storage stability of at least 12 months at 25° C./60% RH (relative humidity) and 30° C./70% RH, preferably at least 36 months at 25° C./60% RH and 30° C./70% RH. However it has also been found that a quantity of reducing sugars of at least 250 ppm has a positive effect on the stability of the active substance. Consequently, a content of a maximum content of 1000 ppm, preferably between 300 ppm and 250 ppm, of reducing sugars in the pharmaceutical solution is to be regarded as being preferred.
  • A drinkable telmisartan solution prepared using a sugar alcohol with a content of reducing sugar of 300 ppm or less does not require any antioxidants or stabilizers, and their addition is thus optional.
  • As the exclusive use of one or more sugar alcohols meets only the USP requirement for adequate preservation, the addition of benzalkonium chloride as a preservative was investigated by way of example for international licensing. The target was to add the smallest possible amount to meet the criteria, in accordance with the requirements laid down by the Pharmacopoeias. It was demonstrated that aqueous drinkable telmisartan solutions in a range of concentrations from 1-10 mg/ml, preferably 1-5 mg/ml, with a pH value of ≥10 or higher, a content of sugar alcohol of 40 percent by weight/volume (% W/V) or more as well as other optional formulation adjuvants above a benzalkonium chloride concentration of 0.005% W/V or higher reliably meet the requirements of the Ph.Eur. as well, while reliably masking the bitter taste of the benzalkonium chloride. Thus on the one hand it is ensured that the requirements of the Ph.Eur. are met and on the other hand the physiological loading is reduced to a minimum.
    • Preparation Process
  • The present invention also describes a process for preparing the drinkable telmisartan solution according to the invention containing 1-10 mg/ml telmisartan, preferably 1-5 mg/ml telmisartan. As far as possible this process also uses methods known from the literature for aqueous solutions to be taken orally.
  • The process is characterized in that a suitable amount of active substance, optionally in the form of a salt or hydrate, is combined with a molar excess of a physiologically acceptable base dissolved in water, in order to obtain a solution with a pH of ≥10. Further formulation adjuvants are optionally added, and the solution is made up with purified water to obtain a concentration range of 1-10 mg of active substance per millilitre of solution. It should be noted that the solution corresponds to the properties already mentioned, particularly that of the pH value of ≥10. Exemplary formulations are presented herein in Examples 1-8.
  • In one particular embodiment a consistency-providing component such as for example a cellulose derivative or PVP is pre-swollen in a given amount of purified water at ambient temperature, then heated to a temperature of 70-80° C. until fully dissolved and then adjusted to a pH of 10 by the addition of the physiologically acceptable base, while the temperature is maintained at 70-80° C. The active substance is then added, with stirring, until a concentration of 1-10 mg/ml is obtained, and the sugar alcohol containing an amount of less than 1000 ppm, preferably less than 300 ppm of reducing sugar is added and dissolved. After the addition and dissolving of the sugar alcohol the solution is cooled to room temperature. Other formulation adjuvants such as synthetic sugar substitutes, flavourings or preservatives are added at RT with stirring. Finally, the pH is restored to 10 using the physiologically acceptable base, before purified water is added to top up to the required weight/volume. Lastly, the solution can be filtered to eliminate particulate impurities, before being transferred into suitable glass or plastic bottles.
  • The drinkable telmisartan solution according to the invention exhibits high stability on storage, which is not limited either by physical instability or by breakdown reactions of the active substance, and in terms of the selected pH it is sufficiently well tolerated physiologically.
  • The drinkable telmisartan solution according to the invention will now be explained by means of the following Examples. The Examples serve only as an illustration and are not to be regarded as restrictive.
    • EXAMPLES Example 1
  • telmisartan 0.2 g
    NaOH 1N 0.68 ml
    maltitol* 60.0 g
    hydroxyethylcellulose 0.1 g
    purified water ad 100 ml
    pH 10
    stability
    25° C./60% RH >12 (18?) months
    30° C./70% RH >12 (18?) months
    Complies with PLT** USP
    according to USP/
    Ph. Eur.
    *≤300 ppm red. sugar,
    **PLT = preservation loading test
    • Example 2
  • telmisartan 0.1 g
    meglumine 0.6 g
    maltitol* 50.0 g
    saccharine-Na 0.6 g
    hydroxyethylcellulose 0.1 g
    purified water ad 100 ml
    pH 10
    stability
    25° C./60% RH >12 months
    30° C./70% RH >12 months
    Complies with PLT** —
    according to USP/
    Ph. Eur.
    *≤300 ppm red. sugar,
    **PLT = preservation loading test
    • Example 3
  • telmisartan 4 mg/ml
    NaOH 1N 0.8 ml
    maltitol* 60.0 g
    hydroxyethylcellulose 0.1 g
    benzalkonium 0.005%
    chloride
    purified water ad 100 ml
    pH 10
    stability
    25° C./60% RH >24 months
    30° C./70% RH >24 months
    Complies with PLT** USP and Ph. Eur.
    according to USP/
    Ph. Eur.
    *≤300 ppm red. sugar,
    **PLT = preservation loading test
    • Example 4
  • telmisartan 0.40 kg/100 L
    NaOH 1N  0.8 kg/100 L
    maltitol* 60.0 kg/100 L
    hydroxyethylcellulose 0.10 kg/100 L
    benzalkonium  0.01 kg/100 L %
    chloride
    purified water ad 100 L
    pH 10
    stability
    25° C./60% RH >24 months
    30° C./70% RH >24 months
    Complies with PLT** USP and Ph. Eur.
    according to USP/
    Ph. Eur.
    *≤300 ppm red. sugar,
    **PLT = preservation loading test
    • Example 5
  • telmisartan 0.1 g
    meglumine q.s. ad pH 10
    maltitol* 70.0 g
    collidone K 25 0.2 g
    purified water ad 100 ml
    pH 10
    stability
    25° C./60% RH >18 (12?) months
    30° C./70% RH >18 (12?) months
    Complies with PLT** USP
    according to USP/
    Ph. Eur.
    *≤300 ppm red. sugar,
    **PLT = preservation loading test
    • Example 6
  • telmisartan 4 mg/ml
    NaOH 1N 0.8 ml
    xylitol* 60.0 g
    hypromellose 0.1 g
    purified water ad 100 ml
    pH 10
    stability
    25° C./60% RH >12 (18?) months
    30° C./70% RH >12 (18?) months
    Complies with PLT** USP
    according to USP/
    Ph. Eur.
    *≤300 ppm red. sugar,
    **PLT = preservation loading test
    • Example 7
  • telmisartan 2 mg/ml
    NaOH 1N 0.68 ml
    sorbitol 60.0 g
    hypromellose 0.1 g
    purified water ad 100 ml
    pH 10
    stability
    25° C./60% RH >18 months
    30° C./70% RH >18 months
    Complies with PLT** USP
    according to USP/
    Ph. Eur.
    *≤300 ppm red. sugar,
    **PLT = preservation loading test
    • Example 8
  • telmisartan (5 mg/ml) 0.5000 g
    NaOH 1.9000 g
    maltitol* 60.000 g
    hydroxyethylcellulose 0.1000 g
    purified water 59.1600 g
    pH 10
    stability
    25° C./60% RH >24 months
    30° C./70% RH >24 months
    Complies with PLT** USP
    according to USP/
    Ph. Eur.
    *≤300 ppm red. sugar,
    **PLT = preservation loading test

Claims (17)

1. A drinkable pharmaceutical solution comprising:
telmisartan or a pharmaceutically acceptable salt, hydrate or polymorph thereof, wherein the telmisartan has a concentration of 1 to 10 mg/ml within the drinkable pharmaceutical solution, and the drinkable pharmaceutical solution has a pH of 10.
2. The drinkable pharmaceutical solution of claim 1, further comprising sodium hydroxide.
3. The drinkable pharmaceutical solution of claim 1, further comprising one or more sugar alcohols selected from the group consisting of maltitol, xylitol, sorbitol, and mannitol, wherein the one or more sugar alcohols have a total concentration of 40 wt. % to 70 wt. % and a maximum content of 2000 ppm of reducing sugar before addition to the drinkable pharmaceutical solution.
4. The drinkable pharmaceutical solution of claim 3, wherein the one or more sugar alcohols have a maximum content of 1000 ppm of reducing sugar before addition to the drinkable pharmaceutical solution.
5. The drinkable pharmaceutical solution of claim 1, further comprising one or more consistency-providing components selected from the group consisting of hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, hypromellose, and polyvinylpyrrolidone (PVP).
6. The drinkable pharmaceutical solution of claim 1, further comprising saccharin-Na.
7. The drinkable pharmaceutical solution of claim 1, further comprising benzalkonium chloride.
8. A drinkable pharmaceutical solution comprising:
telmisartan or a pharmaceutically acceptable salt, hydrate or polymorph thereof, wherein the telmisartan is present in a concentration of 1 to 10 mg/ml within the drinkable pharmaceutical solution;
sodium hydroxide;
one or more sugar alcohols selected from the group consisting of maltitol, xylitol, sorbitol, and mannitol, wherein the one or more sugar alcohols have a total concentration of 40 wt. % to 70 wt. % within the drinkable pharmaceutical solution and a maximum content of 2000 ppm of reducing sugar before addition to the drinkable pharmaceutical solution;
optionally saccharin-Na;
optionally benzalkonium chloride; and
water;
wherein the drinkable pharmaceutical solution has a pH of 10.
9. The drinkable pharmaceutical solution of claim 8, further comprising one or more consistency-providing components selected from the group consisting of hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, hypromellose, and polyvinylpyrrolidone (PVP).
10. A kit comprising a container and the drinkable pharmaceutical solution of claim 1.
11. The kit of claim 10, further comprising a dosing aid for the drinkable pharmaceutical solution.
12. The kit of claim 10, wherein the container is glass or plastic.
13. A method of preparing a drinkable pharmaceutical solution, comprising:
(a) dissolving telmisartan or a pharmaceutically acceptable salt, hydrate or polymorph thereof and one or more sugar alcohols in water and NaOH so as to obtain a pH of 10; and
(b) adjusting the concentration of telmisartan in the solution to 1 to 10 mg/ml.
14. A method of treating hypertension or kidney disease comprising administering a drinkable pharmaceutical solution to a cat, the pharmaceutical solution comprising:
telmisartan or a pharmaceutically acceptable salt, hydrate or polymorph thereof, wherein telmisartan is at a concentration of 1 mg/ml to 10 mg/ml within the pharmaceutical solution, and the drinkable pharmaceutical solution has a pH of 10.
15. The method of claim 14, wherein the drinkable pharmaceutical solution further comprises:
sodium hydroxide;
one or more sugar alcohols selected from the group consisting of maltitol, xylitol, sorbitol, and mannitol;
optionally saccharin-Na;
optionally benzalkonium chloride; and
water.
16. The method of claim 15, wherein the drinkable pharmaceutical solution further comprises:
one or more consistency-providing components selected from the group consisting of hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, hypromellose, and polyvinylpyrrolidone (PVP).
17. The method of claim 14, wherein telmisartan is at a concentration of 1 to 5 mg/ml within the pharmaceutical solution.
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Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1908469A1 (en) 2006-10-06 2008-04-09 Boehringer Ingelheim Vetmedica Gmbh Angiotensin II receptor antagonist for the treatment of systemic diseases in cats
ES2598490T3 (en) 2009-05-20 2017-01-27 Boehringer Ingelheim Vetmedica Gmbh Telmisartan drinkable pharmaceutical solution
JP6377426B2 (en) * 2013-06-21 2018-08-22 わかもと製薬株式会社 Aqueous pharmaceutical composition
JP6344678B2 (en) * 2013-09-27 2018-06-20 キョーリンリメディオ株式会社 Telmisartan-containing preparation and method for producing the same
EA202090205A1 (en) * 2017-07-07 2020-06-02 Бёрингер Ингельхайм Ветмедика Гмбх ANGIOTENZINE II RECEPTOR ANTAGONIST FOR PREVENTION OR TREATMENT OF SYSTEM DISEASES IN CATS
US20230330100A1 (en) * 2022-02-17 2023-10-19 Woolsey Pharmaceuticals, Inc. Taste-masking oral formulations of fasudil

Family Cites Families (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1023027B (en) 1953-07-10 1958-01-23 Hoffmann La Roche Process for the production of polyenedialdehydes
US4448778A (en) * 1981-08-03 1984-05-15 Ici Americas Inc. Maltitol containing gel base systems
US4880804A (en) 1988-01-07 1989-11-14 E. I. Du Pont De Nemours And Company Angiotensin II receptor blocking benzimidazoles
US6028091A (en) 1990-12-14 2000-02-22 Smithkline Beecham Plc Medicament
US5614519A (en) * 1991-02-06 1997-03-25 Karl Thomae Gmbh (1-(2,3 or 4-N-morpholinoalkyl)-imidazol-4-yl)-benizimidazol-1-yl-methyl]-biphenyls useful as angiotensin-II antagonists
JP3862295B2 (en) 1993-09-30 2006-12-27 独立行政法人理化学研究所 Anti-obesity agent
WO1996031234A1 (en) 1995-04-07 1996-10-10 Novartis Ag Combination compositions containing benazepril or benazeprilat and valsartan
WO1997049392A1 (en) 1996-06-24 1997-12-31 Merck & Co., Inc. A composition of enalapril and losartan
EP1058541B1 (en) 1998-03-04 2004-01-28 Takeda Chemical Industries, Ltd. Sustained-release preparation for aii antagonist, production and use thereof
JPH11315034A (en) 1998-03-04 1999-11-16 Takeda Chem Ind Ltd Sustained release preparation of compound having angiotensin ii antagonism, its production and use
US6204281B1 (en) 1998-07-10 2001-03-20 Novartis Ag Method of treatment and pharmaceutical composition
DE19901921C2 (en) 1999-01-19 2001-01-04 Boehringer Ingelheim Pharma Polymorphs of telmisartan, process for their preparation and their use in the manufacture of a medicament
US6358986B1 (en) 1999-01-19 2002-03-19 Boehringer Ingelheim Pharma Kg Polymorphs of telmisartan
DE10018401A1 (en) 2000-04-13 2001-10-25 Boehringer Ingelheim Pharma Medicament for treating hypertrophy-related myocardial disease, containing bradycardic agent, preferably cilobradine, and optionally another cardiac drug
WO2002030400A1 (en) * 2000-10-06 2002-04-18 Takeda Chemical Industries, Ltd. Solid preparations
WO2003013609A1 (en) 2001-08-03 2003-02-20 Takeda Chemical Industries, Ltd. Sustained-release medicines
US6737432B2 (en) 2001-10-31 2004-05-18 Boehringer Ingelheim Pharma Kg Crystalline form of telmisartan sodium
DE10153737A1 (en) 2001-10-31 2003-05-28 Boehringer Ingelheim Pharma Crystalline sodium salt of telmisartan, process for its preparation and its use for the manufacture of a medicament
US7232828B2 (en) 2002-08-10 2007-06-19 Bethesda Pharmaceuticals, Inc. PPAR Ligands that do not cause fluid retention, edema or congestive heart failure
AU2003268219B2 (en) 2002-08-28 2009-09-24 Barnes-Jewish Hospital Conjoint administration of morphogens and ACE inhibitors in treatment of chronic renal failure
DE10244681A1 (en) * 2002-09-24 2004-04-08 Boehringer Ingelheim International Gmbh New solid telmisartan-containing pharmaceutical formulations and their preparation
US8980870B2 (en) * 2002-09-24 2015-03-17 Boehringer Ingelheim International Gmbh Solid telmisartan pharmaceutical formulations
DE10335027A1 (en) 2003-07-31 2005-02-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of telmisartan and simvastatin for treatment or prophylaxis of cardiovascular, cardiopulmonary and renal diseases e.g. hypertension combined with hyperlipidemia or atherosclerosis
US20050187262A1 (en) 2004-01-12 2005-08-25 Grogan Donna R. Compositions comprising (S)-amlodipine and an angiotensin receptor blocker and methods of their use
DE102004008804A1 (en) 2004-02-20 2005-09-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg Multilayer tablet
EP1579862A1 (en) 2004-03-25 2005-09-28 Boehringer Ingelheim Vetmedica Gmbh Use of PDE III inhibitors for the reduction of heart size in mammals suffering from heart failure
WO2005123070A1 (en) 2004-06-09 2005-12-29 Fibrogen, Inc. Dual blockade of renin-angiotensin system reduces connective tissue growth factor levels in diabetic nephropathy
CN100364532C (en) 2004-09-30 2008-01-30 江苏恒瑞医药股份有限公司 Composition containing amlodipine and angiotensin II receptor inhibitor
HRP20140212T1 (en) * 2004-11-05 2014-04-11 Boehringer Ingelheim International Gmbh TWO-LAYER TABLET CONTAINING TELMISARTAN AND AMLODIPINE
US20070026026A1 (en) * 2005-08-01 2007-02-01 David Delmarre Oral liquid losartan compositions
EP1908469A1 (en) 2006-10-06 2008-04-09 Boehringer Ingelheim Vetmedica Gmbh Angiotensin II receptor antagonist for the treatment of systemic diseases in cats
EP1970053A1 (en) * 2007-03-14 2008-09-17 Boehringer Ingelheim Pharma GmbH & Co. KG Pharmaceutical composition
ES2598490T3 (en) 2009-05-20 2017-01-27 Boehringer Ingelheim Vetmedica Gmbh Telmisartan drinkable pharmaceutical solution

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